Oricula Therapeutics Product History

Oricula Therapeutics' first product (ORC-13661), a medicine to preserve hearing during aminoglycoside therapy, is in preclinical development and progressing towards an FDA Initial New Drug (IND) filing.

Current status

Our initial screening hit, ORC-0001 (also formerally known as BPN-0001 and PROTO-1), was effective in zebrafish and rats in protecting hair cells from the toxic effects of aminoglycosides (AGs), but ADMET testing and especially hERG tests showed that the safety margin of ORC-0001 was not adequate to progress it as a medicinal candidate.

Funding provided by NIDCD and the NINDS Blueprint Neurotherapeutics Program (NIH BPN) allowed us to engage in an extensive SAR (structure activity relationship) program. In all, we synthesized and tested 329 analogs of ORC-0001 and found 50 analogs that were 10 times more potent and 10 analogs that were 100 times more potent than the initial lead in protecting zebrafish hair cells. Additional testing and analysis established that five compounds had the selectivity (based on broad screening), potency, efficacy, pharmacokinetic and physiochemical properties along with chemical novelty to advance the project to late lead optimization. In parallel, we confirmed that none of these compounds interfere with the bactericidal efficacy AGs.

University of Washington was awarded a Composition of Matter patent on these and related compounds, and Oricula Therapeutics has an exclusive license from the University to develop and commercialize these assets.

ORC-13661 was chosen as the lead clinical candidate after extensive efficacy testing in using the ABR analysis. ORC-13661 at an oral dose of 5mg/kg/day provided 100 percent protection of hearing for rats treated for 10 days with amikacin at 320 mg/kg/day administered subcutaneously. It also provided almost complete hearing protection for rats treated for 12 days at the same dose of amikacin. Additional testing of ORC-13661 shows that it provides:

  • Adequate oral bioavailability in mice, rats and dogs

  • Linear pharmacokinetics in a range of 0.2 mg/kg - 100 mg/kg

  • A half-life of 4-6 hours, providing adequate coverage for once/day therapy

  • AMES testing demonstrated no evidence of mutagenicity

  • Microsomal and Hepatocyte Clearance consistent with the half-life in serum

  • A metabolic profile similar in rat, dog, monkey and human with no unique human metabolites

  • A NOAEL in the rat 7-day DRF study of > 100 mg/kg, providing a wide therapeutic index

  • Additional in vitro testing showed no interference with aminoglycoside bactericidal effect in P. auruginosa, E.coli, or M.tuberculosis.

Oricula Therapeutics has been awarded a Phase 2 SBIR grant by NIH NIAID to advance ORC-13661 through preclinical safety and toxicology to FDA IND submission.

Hearing Loss Facts


Epidemiology of Hearing

Hearing loss is a serious problem worldwide

  • 48 million people in the U.S. have some degree hearing loss

  • 278 million (2%) worldwide have disabling hearing loss

  • 10-20% patients treated with aminoglycoside antibiotics develop hearing loss

  • 60-80% treated with anti-cancer drug cisplatin develop hearing loss

  • 60% recent U.S. war veterans suffer hearing loss

  • 3:1000 children are born deaf or hard-of-hearing

  • 50:1000 ICU babies have serious hearing loss

There is currently NO available drug that protects against any form of hearing loss

 

Hearing Loss and Balance Disorders Result from Damage to Hair Cells

  • Hair cells are the sensory receptors of the inner ear used to detect sound and perceive bodily motion for balance.

  • There is a direct relationship between hair cell loss and hearing loss and/or balance problems

  • Humans start with only ~15,000 hair cells in each cochlea.

  • When hair cells are lost due to mutation, disease, injury, or exposure to environmental toxins, they are not replaced.

Hair cells do not regenerate in mammals

Aminoglycosides Use


Aminoglycoside antibiotics (AGs) are some of the earliest and most effective antibiotics. They continue to be used worldwide to treat a variety of life threatening bacterial infections including; pulmonary infections in patients with cystic fibrosis, endocarditis, neonatal septicemia, pseudomonas respiratory infections, and multiple drug resistant tuberculosis, among others. However, AG use is associated with ototoxicity that results in some level of permanent hearing loss in as many as 20 percent of the two-to-four million individuals treated with parenteral AGs annually. This serious liability has clearly limited the therapeutic utility of this important class of antibiotics.

Despite this limitation, based on data provided by IMS Health, there are still more than 300 million patient-days of parenteral AGs given worldwide each year.

Market

Annual Doses Parenteral Aminoglycosides

United States

8,000,000

Rest of Developed World

50,000,000

Rest of World

500,000,000

Total Annual Doses

558,000,000

The availability of an adjunct therapy to protect against the ototoxic side effect of AGs would allow AGs to be used worldwide in more cases as a first-line therapy and to treat additional infections where currently they are avoided. We estimate the current market potential for our product could exceed $475 million per year and would grow as AGs become the treatment of choice for additional serious bacterial infections.

Market Opportunity


The market for a hearing protectant will be worldwide. It is expected to be given with all parenteral doses of aminoglycoside (AG) antibiotics. The degree of penetration of use will depend upon our ability to inform prescribers that the product is a safe and cost-effective way of preventing hearing loss. Although the societal costs of hearing loss, especially in children, is huge, one cannot assume that every health care decision is entirely rational. AGs are used in many places because of their low price and health care delivery organizations may not have the budget to add a hearing protectant to the life saving regimen of AGs. So, in our modeling, we have assumed low pricing and lower market penetration. Table 1 provides the annual parenteral doses of different AGs in the U.S., the developed world (not counting the U.S.), and the rest of the world.

55a94f_188f0d5e026e46cd9767d91d4123ce4e.png
 

Use of aminoglycosides

Although we don't know exactly what diseases are treated with these antibiotics, we do know that Amikacin is heavily used for multiple drug resistant tuberculosis (MDR-TB) and is probably why it is used relatively less in the U.S. Tobramycin is heavily used for pseudomonas lung infections and, in the U.S., disproportionately used in Cystic Fibrosis patients. Gentamicin is used widely in the U.S. as a single large dose prior to orthopedic surgeries, but is also used as the first line of treatment for neonatal sepsis until a more targeted antibiotic is determined from culture and sensitivity studies. In the U.S., European Union and other developed countries, AGs are used with caution and only as long as necessary, because of the side effects of the drug. Most parenterally administered antibiotics are given in the hospital setting. And many hospitals require a signoff from an infectious disease physician before AGs can be used. This fact alone would indicate that AGs remain a valuable, life-saving therapy and one in which it can be expected that the availability of a hearing protectant would be immediately embraced and have deep penetration into the practice. 

What price will the market bear?

We have based our projections on the fact that AGs are very inexpensive medications compared to all other antibiotics that might be used as alternatives. The wholesale price of amikacin, tobramycin and gentamicin in the U.S. range from about $5 - $10 per day. The charge to the patient varies widely but $75 - $150 per day would not be an exaggeration. Alternative antibiotics such a beta-lactams, carbapenams, and fluoroquinolones often have wholesale prices of $50 - $300 per day and are often given multiple times during the day, so that the patient charge is proportionately higher. We have conservatively estimated a wholesale price of our protectant at $50/day for the U.S. market, $25 /day for the rest of the developed world and $10/day for the developing world. Based upon these projected prices and assumed market penetration, Table 2 shows the expected annual revenues of the product.

419c5b_c5954c69cbe942b1a50d7ae198ceed15-mv2.png
 

We believe that the worldwide market for our Protectant will exceed $475 million per year by the fifth year of sales.

Evolution of Oricula


Oricula Therapeutics evolved from converging research into hearing loss and compounds that have potential to prevent it. Results of this research identified compounds that protect these cells from ototoxins, specifically aminoglycoside antibiotics known to damage these cells. This research and its resulting patents created the foundation for Oricula Therapeutics.

Key company and product milestones:

  • Novel screening method using zebrafish developed at University of Washington

  • Research using the aminoglycosides class of antibiotics (AGs) as ototoxins leads to identification of a compound that protects hair cells in zebrafish, ORC-0001

  • Auditory Brainstem Response in rats demonstrates mammalian efficacy of ORC-0001

  • Method of Use Patent awarded to University of Washington for protectant compound ORC-0001

  • NINDS Blueprint Neurotherapeutics Program (NIH BPN) Research Grant awarded

  • Drug discovery and pharmeceutical industry expertise added to team

  • Structured Activity Relationship (SAR) and ADME research identifies five analogs to ORC-0001 that are order-of-magnitude more potent, effective, and possess excellent pharmacokinetics and safety profiles

  • Composition of Matter Patent for ORC-0001 analogs applied for by University of Washington

  • Oricula Therapeutics LLC founded

  • Patents for Method of Use and Composition of Matter exclusively licensed from University of Washington by Oricula Therapeutics

  • Washington State Life Sciences Development Fund awards University of Washington grant to fund mammalian efficacy testing of BPN analogs

  • Oricula Therapeutics awarded a Phase 1 SBIR by NIH NIDCD to study safety of ORC-13661

  • Oricula Therapeutics awarded a Phase 2 SBIR by NIH NIAID to advance ORC-13661 to FDA-IND